The long-term goal of this project is to better understand the pathogenic role of anti-carbohydrate antibodies in peripheral neuropathies and related neurological disorders and to develop rational and effective therapeutic strategies to these debilitating diseases. Previous studies have demonstrated that in patients with peripheral neuropathy and paraproteinemia, glycolipid/glycoprotein antigens that bear the epitope HNK-1 (CD57 or SGA) are involved. The structures of the glycolipid antigens were characterized in our laboratory as sulfoglucuronosyl glycolipids (SGGLs). Antibodies against SGGLs are involved in the pathogenesis of immune-mediated peripheral neuropathies because: a). the antigens are localized in PNS myelin and axolemma; the degeneration of which accounts for the loss of sensory and motor functions; b). animal models of peripheral neuropathies can be established using pure glycolipid antigens; c). an antibody-mediated, complement-dependent demyelinating and axonal degenerating process has been established in animals models; d). the presence of SGGLs in endothelial cells (ECs) provides a mechanism that accounts for an antibody-mediated breakdown of the blood-nerve barrier (BNB); and e). the upregulation of the expression of SGGLs is effected by treatment of the ECs by inflammatory cytokines, such as IL-1beta, resulting in greater attachment of leucocytes to the EC surface. Emerging evidence has indicated that other anti-carbohydrate antibodies may be involved in similar neurological disorders, such as anti- GM1 in Guillain-Barre syndrome. Since most of these disorders have antecedent infections, we propose a unified hypothesis (molecular mimicry) regarding anti-carbohydrate antigens by examining the nature of other potential glycoconjugate antigens, particularly bacterial lipopolysaccharides, that share common carbohydrate epitopes in nerve. We will examine the origin of the anti-carbohydrate antibodies and the involvement of these glycoconjuates in eliciting autoimmune responses in animal and man. Since abrogation of the BBB and BNB is a prerequisite of immune-mediated neurological disorders, we will examine the biological function of ECs in the maintenance of BBB and BNB function in normal and pathological conditions. We will develop a new class of anti-inflammatory agents using antisense techniques to suppress the expression of glycoconjugate adhesion molecules to prevent inflammatory T cells and circulating antibodies from attachment to the vascular bed. We will also devise peptide mimics of anti-carbohydrate antibodies by phage display techniques for the treatment for anti-carbohydrate antibody-induced neuropathies and related neurological disorder.